Welcome to part three and the final part of our SENS Undoing Aging 2018 interview; we have a few more scientific questions today for Aubrey and his team as well as questions about future developments and taking new therapies to market.
Dr. de Grey, has your position on the relevance of telomere attrition changed since you first devised SENS, especially in the light of the recent results with fibrosis and your involvement with AgeX?
Aubrey: No. Let’s start with the big picture. Neither I nor anyone sensible has ever suggested that telomere attrition has no functional effects in aging: telomere attrition causes cells to become senescent and runs down the proliferative capacity of stem cells, amongst other things. Nor have I suggested that there wouldn’t be some short-term health benefits to activating telomerase or telomerase gene therapy in aging animals or animal models of age-related disease (or even their human equivalents). Indeed, there was plenty of animal data to support this long before the recent results with a mouse model of idiopathic pulmonary fibrosis (IPF)[1].
The issue is rather that those short-term benefits come with the longer-term (and sometimes not so long-term) risk of increased rates of cancer — something that has been in multiple animal studies (also here, here, here and here) as well as in human epidemiology.
So, why don’t we see a plague of excess cancers in animal studies that show the benefits of telomerase-based treatments? Depending on the study, it’s one or more of four reasons. The most common one is that such studies are usually too short-term: a few weeks or months, which is long enough for the benefits of mobilizing stem cells to help repair some particular problem in an aged or disease-model mouse, but not long enough for a precancerous lesion to erupt into mature clinical cancer. This was true in the IPF study you reference, which lasted just eight weeks [1].
A related issue is that many of these studies involving animal models of age-related disease are actually done in quite young animals that have been damaged in some way that simulates aspects of an age-related disease. Because such animals are still quite young, they haven’t yet lived long enough to have accumulated a high burden of the kinds of mutations that predispose cells to become cancerous, so it’s much less likely that telomerase will enable precancerous cells to develop into full-blown cancers. This, again, was true in the IPF study, which involved animals that were little furry teenagers, only 8-10 weeks old [1]. By contrast, the average age of onset of human IPF is 67, and nearly all human IPF patients are over the age of 50. (We’ll get into how they made these adolescent mice develop something resembling IPF a little further along).
At the ages when IPF and other age-related pathology that might otherwise benefit from telomerase treatments emerge in humans, the human body has already acquired multiple cancer-disposing lesions, and most people harbor precancerous cells in their breasts, prostate, and elsewhere. Indeed, autopsy studies show that 30-45% of men who die of other causes in their fifties have actual prostate cancers in their bodies, not just precancerous lesions; their disease just hadn’t yet become aggressive enough to kill them before something else did [2].
Extended over the decades of current human middle age and into the early period of lifespans extended by the first rejuvenation biotechnologies, telomerase activation can be strongly expected to give precancerous and indolent cancerous cells that might otherwise have run out of replicative steam the extra rounds of proliferation needed to gain the mutations that will turn them malignant and ravage the body. Again, this is what we actually see in longer-term studies in aging mice administered extra telomerase and in humans with more permissive telomerase variants.
A third reason why many animal studies of telomerase treatments don’t result in high reported rates of cancer is that the animals may actually be deficient in telomerase to begin with, such that telomerase gene therapies actually just restore the normal activity of telomerase in the animals. This again was a feature of the mouse IPF study: these were mice with their normal telomerase genes completely knocked out, which were then bred for two additional generations to progressively wear down the residual telomeres in their stem cells (and then had DNA-damaging bleomycin applied down their tracheas to their lungs to boot!) [1]. In fact, their original publication reporting that this generated a working model of IPF was even entitled “Mice with pulmonary fibrosis driven by telomere dysfunction”! [3]
When you start off by taking the normal telomerase gene away from a mouse, it’s not exactly surprising that putting that same telomerase gene back in the same mouse ameliorates its short-telomere-driven pathology. The same was true of another study in telomerase-deficient mice that was widely and mistakenly reported in the popular press as showing the “rejuvenating” effects of telomerase therapy [4].
Finally, a significant number of studies where telomerase treatments are shown to have benefits and aren’t reported to have high rates of cancer are done in animals that are made cancer-resistant by other means, such as by giving them extra copies of cancer-resistance genes [5] or by imposing CR on them [6].
The solution to problems caused by age-related attrition of telomeres is not to juice up telomerase to lengthen them again in often-damaged stem cells, but to take telomerase out of the picture, purge those defective stem cells, and replenish stem cell pools periodically with cancer-proofed, pristine replacement cells that are unable to replicate out of control.
Could someone from SENS explain why phiC31 integrases are still important in the age of CRISPR? Looking at the Calos Labs webpage, it is not clear that there is any real advantage to using phage integrases.
Aubrey: Let’s start with what the CRISPR/Cas9 system is good for before explaining why it won’t be much help for rejuvenation biotechnology. CRISPR/Cas9 is an amazing tool for making relatively modest edits in existing genes in isolated cells. This makes it great for things where we can take a few of a patient’s cells out of his or her body, correct a mutation or make similar minor changes, and then reintroduce them. So, for instance, it’s incredibly powerful for genetic diseases involving blood cells, because we can take out some of a patient’s bone marrow stem cells, make the minor edits required to correct the genetic defect, and then wipe out the patient’s original, defective bone marrow using chemotherapy and repopulate it with modified stem cells, which will then replace the entire blood cell system.
It can also be used to create mutant animal models, by making minor edits in embryos (which are, again, single cells or only a few of them) and then growing out a mature organism, every one of whose cells contains the modified gene. And as the technology matures, and with better delivery systems, it could also be used to correct other relatively minor mutations that cause very early-onset versions of diseases of aging, like the ApoEε4 allele (which greatly speeds the onset and course of Alzheimer’s disease) or the BRCA1 and BRCA2 mutations that put one at higher risk for breast, ovarian and possibly prostate cancer.
But in order to deliver rejuvenation biotechnologies, we need to do something quite different: deliver large, entirely new genes across tissues still in the body. For such purposes, CRISPR/Cas9 is really not much help. (For some of the technical details on why, see here — skip down to “As to the CRISPR/Cas9 system”). Reserchers are working to improve on all of CRISPR/Cas9’s limitations, but it’s not at all clear that it will ever be able to go as far as needed for most rejuvenation biotechnologies. Calos’ webpage doesn’t highlight the key contrast the way we do because, as it stands, it’s a bit of a moot question; we can’t use the phiC31 integrase clinically because we don’t have the needed “landing pads” for the integrase in our cells. And that’s exactly what the second stage of the Maximally-Modifiable Mouse project is for: to eventually engineer those “landing pads” into all of our cells, at which point we’d be able to use the integrase for safe, reliable delivery of arbitrarily-large new genes across adult tissues.
You have been engineering glucosepane-eating bacteria that use enzymes effectively ‘gifted’ to them. Have the enzymes you identified demonstrated specificity to glucosepane?
Aubrey: We can say that Dr. David Spiegel’s SRF-funded lab at Yale has identified some candidates, but we can’t go into the details at this time.
Dr. de Grey, can you make any estimates as to the name and/or date of creation of the company spun out to market glucosepane breakers?
Aubrey: First, to break this down a bit: spinoff companies don’t actually market therapeutics; they don’t have the size or the resources (legal, clinical, or financial) to run the large-scale phase III clinical trials required to gain licensure from the FDA and similar regulators around the world and then mass-manufacture a therapy for global distribution, this latter being especially challenging for biologicals like antibodies and cell therapies (which is the form that most rejuvenation biotechnologies will take, as opposed to conventional small-molecule drugs). So, we wouldn’t be literally spinning out a company to market glucosepane breakers. The spinoff will take research that has identified a strong candidate glucosepane-breaker and demonstrated its efficacy in initial proof-of-concept research and do some further R&D (perhaps taking it as far as initial phase I trials) until they are ready to begin courting the large pharma/biotech players who bring their much larger resources and wider expertise to bear in late-stage clinical development and marketing.
As mentioned in response to another question, Dr. David Spiegel’s SRF-funded research has identified some early-stage candidates, but none that are solid enough for a spin off company just yet; that said, do expect some news on the commercialization front in the glucosepane space in coming months.
A question for Dr. O’Connor about MitoSENS: We recently heard that your team was close to four of the thirteen genes. Can you tell us how you are progressing with the mitochondrial gene transfers?
Oki: We are working on several other genes. Nothing solid enough to announce yet, but I think we’ll have some new things to announce at Undoing Aging 2018.
Dr. O’Connor, has anyone else than SRF tried to replicate the results of your 2016 paper on allotopic expression or tried to do the same with other mitochondrial genes?
Oki: I’ve passed our materials on to several researchers who have requested them, and we also made our plasmids publically available through Addgene. So, it looks like there is some interest in repeating our work, but I haven’t heard about any results yet.
RMR, or robust mouse rejuvenation, is intended to be a SENS implementation that is complete enough to double the remaining life expectancy of an elderly mouse, as demonstrated and then replicated in rigorous laboratory studies. Given the current state of research and funding and the current rate of progress, what is the expected timeframe for RMR?
Aubrey: This is difficult to say, and, as you say, is always heavily dependent on funding levels. So far, insufficient funding has held us back to going less than half as fast as I had predicted was possible with full funding. Granted adequate funding going forward, a reasonable if still-speculative estimate would be seven years.
Given the state of immunotherapy, and taking into account the rate of progress in the field, how confident are you that OncoSENS may be unnecessary? Even if not soon, do you think it’s possible that cancer could ever be completely defeated without implementing OncoSENS, i.e. without deleting the telomerase and ALT genes?
Aubrey: The recent progress in cancer immunotherapy has certainly made me much more optimistic than I was five years ago that new cancer therapies might hold off cancer for more than a very small number of years — but not that it might make WILT redundant. If we had all the other components of a comprehensive panel of rejuvenation biotechnologies assembled and deployed, ongoing progress with these therapies might well give us a slightly longer runway along the path to “longevity escape velocity” than I had expected at the time. But only slightly; within an all-too-short few additional years, I expect that without WILT, the surging rocket of “longevity escape velocity” will still run headlong into a wall of cancer until we have a way to definitively defeat its evolutionary engine of selection and replication. At present, WILT is the sole foreseeable approach to doing that.
What single item or reagent used in research (exempting wages) costs the most across research projects?
Aubrey: Probably Fetal Bovine Serum. It’s necessary for all cell culture projects, and you can’t skimp on the price since cells are so sensitive — and no one has figured out how to make it well without requiring the expensive initial animal involvement.
SRF showed that it is possible to degrade oxidized cholesterol using external enzymes from bacterial sources. Has there been any other progress in this direction? In other words, how is LysoSENS research progressing against this particular kind of intracellular aggregate?
Aubrey: We licensed out the original research to which you refer several years ago, and we don’t have much visibility into what the company in question is up to. I can also say that we’re aware of a very promising LysoSENS project working at the problem from a quite different and novel angle, but can’t make any announcements at this time.
Which rejuvenation treatments can we reasonably expect to reach the clinic first? Assuming ideal conditions, when could the more easily implementable among them be expected to be tested and approved for human use?
Aubrey: If you don’t count stem cell therapies (some of which are in clinical use, but not as rejuvenation biotechnology), it’s a race between ablating senescent cells with senolytics (with UNITY Biotechnology expected to perform their first-in-human trials early next year) and one of the many immunotherapies targeting the intracellular or extracellular aggregates that drive the neurodegenerative diseases of aging.
When a branch of the basic research done at SENS goes far enough that it becomes commercially interesting and could spawn a new therapy, is it conceivable to convert SENS to a for-profit organization and seek investments? Why do you choose to start new companies instead of taking the Elon Musk approach of using discoveries for profit and financing basic research with the money? Would it be possible to only involve investors who understand this vision?
Aubrey: The Foundation itself won’t become a for-profit organization, though we have, in the past, spun out individual projects as startups or sold them to investors once they were ripe enough to be carried forward on that basis, and we will continue to do so in the future. Examples include licensing our funded LysoSENS project on 7-ketocholesterol to Human Rejuvenation Technologies, Inc. and licensing our LysoSENS project on A2E to Ichor Therapeutics.
We also provided seed capital to senescent cell ablation startup Oisín Biotechnologies, and work that we have supported was also the basis of the MitoSENS technology behind Gensight Biologics; the AmyloSENS technology targeting senile cardiac amyloidosis that is part of Covalent Bioscience’s portfolio; and Revel LLC, which is in the process of commercializing products emerging from Dr. David Spiegel’s SRF-funded research on glucosepane at Yale. Once these therapies are turned into therapies that are on the market and earning revenues, we will earn royalties and similar monies which we’ll roll into other important areas of SENS research.
However, the Foundation itself will not become a for-profit venture, because doing so would interfere with our ability to pursue our mission: to catalyze the development of a comprehensive platform of rejuvenation biotechnologies. While we’re always looking for opportunities for true blind spots in rejuvenation biotechnologies that can be quickly nudged into proofs-of-concept ready to be spun out into startups with just a little more support, it’s also critical that we invest in planks of the SENS platform that are in much earlier stages of development. And it’s essentially impossible to run a sustainable for-profit enterprise doing such early-stage research. Investors don’t have the patience for the long lead times and uncertainty that yawns between putting down the money and an IPO or full-on commercialization.
Even the true giants of the legacy pharmaceutical industry — who were once able to support significant amounts of relatively early-stage work in-house because of their enormous budgets and soaring profitability — have been in rapid retreat from that model for decades now, shutting down in-house research campuses in favor of buying up startups. On the other end, Elon Musk’s admirable and disruptive ventures — SpaceX, Tesla, and SolarCity — are doing mission-driven work in commercializing and innovating technologies that were already on the market, the early-stage work having already been done (and continues to be done) in university labs, the National Laboratories, and Advanced Research Projects-Energy (ARPA-E).
The best places for early-stage work to be done has always been university labs or not-for-profit research facilities supported by major government health institutes like the NIH, or by philanthropy, where the funding can be allocated and lines of research pursued based on merit and long-term considerations free from investor pressures.
Additionally, a critical part of our work in getting us to a future beyond degenerative aging is our efforts to nurture an entire rejuvenation biotechnology ecosystem, not just the direct sponsorship of research projects aimed at developing individual therapies. This is why we place young students into opportunities for rejuvenation research as part of their academic training through SRF Education; why we bring together academic researchers working in disparate strands of rejuvenation research who labor in ignorance of each others’ work at the Strategies for Engineered Negligible Senescence conferences (and the upcoming Undoing Aging conference); and why we bring some of those same researchers together with investors and the existing biotech industry at the more industry-oriented Rejuvenation Biotechnology conference series. Such work simply can’t be justified to venture capitalists looking for the next IPO payout.
Similarly, companies already close to SENS, such as Unity, could apply the strategy of funding more basic research using profits. Are any of these companies planning to do this?
Aubrey: Note that in this case, UNITY Biotechnology is supporting additional work on the intellectual property that they have themselves licensed from Campisi’s and others’ labs, and on small molecules that they have acquired and identified independently of any of the investigators whose IP they have licensed; they are not disbursing funds that can be reallocated into other kinds of research, which (again) is key to the ongoing progress of SRF. That’s a model to which we’re certainly open, and we will negotiate on a case-by-case basis as opportunities arise.
Once a significant part of the science work behind rejuvenation has been done and spun off to other companies, does SRF plan to fade out, or is there any plan to work with policy-makers and institutions to ensure rapid and widespread access to rejuvenation treatments?
Aubrey: The latter! However, the moment to make the shift from development to distribution and access is likely somewhat later in the process than when you suggest; depending on how the industry evolves, it would more likely be either when it is clear that the “damage-repair” heuristic of SENS has become accepted as the dominant paradigm for tackling diseases of aging or when the individual components of a comprehensive panel of rejuvenation biotechnologies have all been licensed and are being used to treat people who do not yet have obvious age-related pathology. At that point, the research needed to carry us forward will be self-sustaining, and the pressing issue of the day will be making sure that therapies become widely and justly available as rapidly as possible.
We would like to thank Dr. Aubrey de Grey and the SENS Research Foundation team for taking the time to answer all these questions, and we look forward to catching up with you again in the near future. You can find part one and part two of this interview by following the linked text.
Literature
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[2] Martin, R. M. (2007). Commentary: Prostate cancer is omnipresent, but should we screen for it?. International journal of epidemiology, 36(2), 278-281.
[3] Povedano, J. M., Martinez, P., Flores, J. M., Mulero, F., & Blasco, M. A. (2015). Mice with pulmonary fibrosis driven by telomere dysfunction. Cell reports, 12(2), 286-299.
[4] Jaskelioff, M., Muller, F. L., Paik, J. H., Thomas, E., Jiang, S., Adams, A. C., … & Horner, J. W. (2011). Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature, 469(7328), 102.
[5] Tomás-Loba, A., Flores, I., Fernández-Marcos, P. J., Cayuela, M. L., Maraver, A., Tejera, A., … & Viña, J. (2008). Telomerase reverse transcriptase delays aging in cancer-resistant mice. Cell, 135(4), 609-622.
[6] Vera, E., de Jesus, B. B., Foronda, M., Flores, J. M., & Blasco, M. A. (2013). Telomerase reverse transcriptase synergizes with calorie restriction to increase health span and extend mouse longevity. PLoS One, 8(1), e53760.
